Role of CXCR2/CXCR2 ligands in vascular remodeling during bronchiolitis obliterans syndrome.
Role of CXCR2/CXCR2 ligands in vascular remodeling during bronchiolitis obliterans syndrome.
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DOI：
10.1172/jci24233
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发表时间：
2005-05
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影响因子：
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通讯作者：
J. Belperio;M. Keane;M. Burdick;B. Gomperts;Y. Xue;Kurt M. Hong;J. Mestas;A. Ardehali;B. Mehrad;R. Saggar;J. Lynch;D. Ross;R. Strieter
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作者：
J. Belperio;M. Keane;M. Burdick;B. Gomperts;Y. Xue;Kurt M. Hong;J. Mestas;A. Ardehali;B. Mehrad;R. Saggar;J. Lynch;D. Ross;R. Strieter
血管生成和血管重塑支持纤维增生过程；然而，在肺移植后发生的毛细支气管炎闭塞综合征（BOS）期间，没有研究解决血管生成在同种异体移植气道纤维闭塞期间的重要性。ELR(+) CXC趋化因子介导中性粒细胞募集和促进血管生成。它们共享的内皮细胞受体是g偶联蛋白受体CXC趋化因子受体2 （CXCR2）。我们发现，多种ELR(+) CXC趋化因子水平升高与BOS的存在相关。使用小鼠BOS模型进行的概念验证研究不仅显示了早期中性粒细胞浸润，而且在气管同种异体移植物中也显示了血管重塑。此外，即使在没有明显中性粒细胞浸润的情况下，气管移植物ELR(+) CXC趋化因子也持续表达，并且在气管移植物纤维闭塞过程中与血管重构存在暂时性关联。此外，在中和研究中，抗cxcr2抗体抑制早期中性粒细胞浸润和后期血管重塑，从而导致小鼠BOS的衰减。当CXCR2（-/-）小鼠接受环孢素A治疗时，纤维闭塞的衰减更明显。这支持了CXCR2/CXCR2配体生物轴在BOS过程中具有双峰功能的观点：早期，它对中性粒细胞募集很重要，而后期，在纤维闭塞期间，它对独立于中性粒细胞募集的血管重塑很重要。
Angiogenesis and vascular remodeling support fibroproliferative processes; however, no study has addressed the importance of angiogenesis during fibro-obliteration of the allograft airway during bronchiolitis obliterans syndrome (BOS) that occurs after lung transplantation. The ELR(+) CXC chemokines both mediate neutrophil recruitment and promote angiogenesis. Their shared endothelial cell receptor is the G-coupled protein receptor CXC chemokine receptor 2 (CXCR2). We found that elevated levels of multiple ELR(+) CXC chemokines correlated with the presence of BOS. Proof-of-concept studies using a murine model of BOS not only demonstrated an early neutrophil infiltration but also marked vascular remodeling in the tracheal allografts. In addition, tracheal allograft ELR(+) CXC chemokines were persistently expressed even in the absence of significant neutrophil infiltration and were temporally associated with vascular remodeling during fibro-obliteration of the tracheal allograft. Furthermore, in neutralizing studies, treatment with anti-CXCR2 Abs inhibited early neutrophil infiltration and later vascular remodeling, which resulted in the attenuation of murine BOS. A more profound attenuation of fibro-obliteration was seen when CXCR2(-/-) mice received cyclosporin A. This supports the notion that the CXCR2/CXCR2 ligand biological axis has a bimodal function during the course of BOS: early, it is important for neutrophil recruitment and later, during fibro-obliteration, it is important for vascular remodeling independent of neutrophil recruitment.